BackgroundAlzheimer's disease (AD) is the most common cause
of cognitive impairment in the elderly, with About 6%
of people aged over 65 years having some form of dementia;
the incidence of AD doubles every five years after the
age of 60 years,being rare before this age, and afflicts
approximately 4 million people in the US. Dementia is
rare before the age of 60 years.

Alzheimer's disease (AD) is considered a type of
dementia demonstrating insidious onset and slow deterioration,
and involving impairment of speech, motor, personality,
and executive function.

Vascular dementia is considered a multi-infarct
(multiple areas of brain have been injured due to inadequate
blood supply) dementia involving stepwise deterioration
of executive function - possibly with language and motor
dysfunction - resulting from cerebral arterial occlusion.
Vascular dementia usually occurs in the presence of vascular
risk factors such as diabetes, hypertension, and smoking,
and generally has a more sudden onset and stepwise progression
than Alzheimer's disease.

Screening/Diagnosis
In 2003, the US preventive Services Task Force (USPSTF
(2003): Screening
for Dementia - Recommendations and Rationale)
emphasized the importance of early recognition of cognitive
impairment, noting that although current evidence does
not support routine screening of otherwise symptomless
patients or ones unsuspected of such impairment, nonetheless
clinicians should assess cognitive function whenever cognitive
impairment or deterioration is indeed suspected, based
on direct observation, patient report, or concerns raised
by family members, friends, or caretaker.

As to testing, the USPSTF determined that there are "some
screening tests have good sensitivity but only fair specificity
in detecting cognitive impairment and dementia",
and that furthermore after examining the numerous diagnostic
tests for AD and dementia available, the Mini-Mental Status
Examination (MMSE) is the best-studied instrument for
screening for cognitive impairment (for an online version
of the Standardized MMSE, see International Psychogeriatric
Association (IPA): SMMSE),
although (1) the predictive value of a positive result
is only fair, and (2) its accuracy depends upon a person's
age and educational level. In addition, tests that assess
functional limitations rather than cognitive impairment,
such as the Functional Activities Questionnaire (FAQ),
can detect dementia with sensitivity and specificity comparable
to that of the MMSE (for the online FAQ and other AD-diagnostic
tests, see IPA: A
Guide to the Diagnosis and Assessment of Alzheimer's Disease).
See also Karlawish and Clark, Ann Intern Med (2003): Diagnostic
Evaluation of Elderly Patients with Mild Memory Problems,

Etiology/Risk
Factors
Although the precise cause of Alzheimer's disease is to
date unclear, a critical pathological process appears
to be the deposition of abnormal amyloid in the central
nervous system. In addition, the majority of patients
with the relatively rare condition of early onset Alzheimer's
disease (onset before age 60) show an autosomal dominant
inheritance due to mutations on amyloid precursor protein
genes or presenelin; in this connection, the APP, PS-1,
and PS-2 genes have been identified. Furthermore ,later
onset dementia can demonstrate some clustering in families,
although here specific gene mutations have not yet been
identified. Head injury, Down's syndrome, and lower premorbid
intellect may be risk factors for Alzheimer's disease.
Vascular dementia is related to cardiovascular risk factors,
such as smoking, hypertension, diabetes, and more recent
evidence suggesting also elevated homocysteine levels.

More particularly, Alzheimer's disease appears characterized
by (1) the microscopic development of senile plaques
between neurons, and (2) neurofibrillary tangles
within neurons, which are associated with neuronal destruction,
especially in cholinergic neurons.

As to the senile plaques, these are composed of b-amyloid
polypeptides, seem to form as a result of disorders in
processing b-amyloid and its precursor protein, probably
consequent to a combination of both genetic predisposition
and environmental influences It is speculated that one
of these contributory influences may be subclinical ischemia,
given that patients who are hypertensive as well as those
with elevated cholesterol levels, tend to be at increased
risk for Alzheimer's disease.

As to neurofibrillary tangles, these are partially composed
of a protein called tau; tau links together to form filaments,
with the density of these filaments within brain neurons
being directly related to the severity of dementia. Why
tangles form, and whether the tangles are linked to plaque
formation, is as yet unclear, although it is known that
different alleles of a gene create forms of tau more likely
to tangle. However, the ultimate effect of the neurofibrilliary
tangle formation is compromise of microtubular function
and eventual destruction of the neuron. The involvement
of cholinergic neurons in this process causes levels of
acetylcholine within synapses to decline, with an accompanying
drop in levels of acetylcholinesterase (possibly as compensation
for the acetylcholine loss). Along with this is an increase
in the the activity of still another cholinesterase enzyme
called butyrylcholinesterase, which metabolizes a significant
portion of acetylcholine as the disease progresses, eventually,
leading to neuron destruction.

Evidencewatch Commentary
However, Evidencewatch notes that the underlying cholinergic
hypothesis of AD presents some serious conceptual and
methodological problems (see especially Shanks and Venneri
(Am J Geriatr Psychiatry (2005): Conventional
Trial Designs Offer Limited Clinical Understanding of
Cholinesterase-Inhibitor Treatment Effects in Alzheimer
Disease), not adequately accounting for the observed
clinical evidence of some treated patients deteriorating
more rapidly than untreated ones, nor for the manifest
wide variations in the presence and extent of individual
responses. It may be that studies are collecting highly
heterogeneous populations exhibiting marked variation
in regional cerebral blood flow, regional atrophy, and
modular cognitive dysfunction, and this may be fundamentally
confounding.

In addition, the current therapeutic strategy of Alzheimer's
disease therapy informing AChEI use is the targeting of
cholinergic neurotransmitter pathways. However, autopsy
and other pathological findings fail to find predicted
cholinergic degeneration in at least 25% of cases, and
it may be that such degeneration emerges only after the
progression of AD beyond initial stage (Farlow, Geriatrics
(2004): NMDA
receptor antagonists. A new therapeutic approach for Alzheimer's
disease [pdf]), suggesting that the disruption
of cholinergic neurotransmission, although undeniably
an important function in AD, is nonetheless not the whole
story, and other processes involving (1) inflammatory
pathways, (2) oxidative injury or stress, and (3) NMDA
receptor-mediated glutamate excitotoxicity inducing neuronal
loss (as suggested by the evidence for the clinical benefit
of NMDA receptor antagonists) may ultimately be more fundamental.

Newer alternative approaches to blocking the pathological
accumulation of the neurotoxic amyloid beta peptide in
the brain are beginning to emerge: so for instance, passive
immunotherapy appears to block cognitive decline in patients
with Alzheimer's disease; to date the only preparation
of human anti-amyloid beta peptide antibodies reported
to reverse cognitive defects in patients with sporadic
Alzheimer's disease is polyclonal anti-amyloid beta peptide
antibodies contained in human IVIg, but research is in
very early stage (see Weksler, Immun Ageing (2004): The
immunotherapy of Alzheimer's disease).

Most guidelines for monitoring drug therapy in patients
with Alzheimer's disease recommend periodic measurements
of cognition and functional ability. The guidelines generally
advise discontinuing therapy with acetylcholinesterase
inhibitors when dementia becomes severe, although the
evidence for this practice is not definitive.

Acetylcholinesterase
inhibitors (AChEl)
Given that brain acetylcholine activity is reduced in
many forms of dementia, with the level of reduction correlating
with cognitive impairment, several AD treatments enhance
cholinergic activity, notably the use of acetylcholinesterase
inhibitors, which inhibit the degradation of acetylcholine
within synapses, and which have become the mainstay of
AD therapy, being until recently the only available treatment
in the United States for patients with mild to moderate
AD. For most patients, these inhibitors help maintain
cognitive and functional abilities and may also confer
beneficial behavioral effects. The balance of the evidence
suggests that acetylcholinesterase inhibitors are effective,
although as noted the magnitude of benefit is typically
greater in clinical trials than in actual practice, and
at present the balance of the evidence does not support
a finding of significant differences between these agents
(López-Pousa et al., Dement Geriatr Cogn Disord
(2005): Differential
Efficacy of Treatment with Acetylcholinesterase Inhibitors
in Patients with Mild and Moderate Alzheimer's Disease
over a 6-Month Period). The drugs clearly improve
cognition, although their benefits in delaying nursing
home placement and improving functional ability and behaviors
is not as robustly demonstrated.

The three major acetylcholinesterase inhibitors currently
in use are donepezil (Aricept), approved
in 1996; rivastigmine (Exelon), approved
in 2000, and galantamine (the prescription agent
Razadyne, formerly Reminyl, also available
as a nonprescription standardized herbal product), approved
in 2001, with a fourth tacrine (Cognex),
approved in 1993, no longer widely used due to serious
adverse effects including liver damage. The three major
agents have been demonstrated to be safe (see Lanctot
et al, CMAJ (2003): Efficacy
and safety of cholinesterase inhibitors in Alzheimer's
disease: a meta-analysis, and AHRQ Evidence Report/Technology
Assessment (2004): Pharmacological
Treatment of Dementia). Although all may have
potentially troublesome cholinergic side effects (nausea,
anorexia, diarrhea, vomiting, and weight loss), these
adverse reactions are often self-limited with tolerance
developing, and can typically be minimized by slow drug
titration.

Finally, two open label trials shed further light on
the role of rivastigmine in AD therapy. One open label
RCT in people with mild to moderate Alzheimers
disease found cognitive function at 12 weeks to not
differ significantly between rivastigmine and donepezil,
although more patients in the rivastigmine group withdrew
from the trial for any cause. In the second Farlow &
Lilly (BMC Geriatr (2005): Rivastigmine:
an open-label, observational study of safety and effectiveness
in treating patients with Alzheimer's disease for up
to 5 years) note the limitation that much of
the data supporting the safety and efficacy of cholinesterase
inhibitors such as rivastigmine are available for treatment
up to 1 year, with limited data up to 2 1/2 years; their
study found that long-term cholinesterase inhibition
therapy with rivastigmine was well tolerated, with no
dropouts due to adverse effects past the initial titration
period, and that furthermore early initiation of treatment,
with titration to high-dose therapy (46 mg. bid)
may confer some benefit in delaying long-term progression
of the disease and its symptoms.

Galantamine
Several RCTs included in a systematic review (Loy &
Schneider, Cochrane Database Syst Rev (2006): Galantamine
for Alzheimer's Disease) of seven trials with
a total of 3777 subjects found that galantamine consistently
improved cognitive function and global clinical state
over 6 months compared with placebo in people with Alzheimers
disease or vascular dementia. And In a later two month,
open-label extension of an earlier five month, double-blind,
placebo-controlled trial with a 6-week withdrawal phase,
Lyketsos et al. (Am J Geriatr Psychiatry (2004): Long-Term
Outcomes of Galantamine Treatment in Patients With Alzheimer
Disease) showed that galantamine treatment was
maintained cognitive function up to at least 14 months.

In addition, one of the trials studied found that It
appears that doses of 16 mg/d were the best tolerated,
and given that this dose showed statistically indistinguishable
efficacy with higher doses, it would appear the most
most preferable at initiation of therapy.

And although, as the authors note, previous controlled
trials have demonstrated galantamine's positive effect
on cognition, activities of daily living, behavior and
global condition,the study of Bruno Vellas and coresearchers
(Curr Med Res Opin (2005): Early
onset effects of galantamine treatment on attention
in patients with Alzheimer's disease) is the
first to suggest that galantamine may specifically improve
attention in patients with AD, and consequently was
able to improved caregiver stress, time spent caring
for patients and patients' interactions with others
(see also below our discussion of reduction of caregiver
burden).

Galantamine and Reduction of
Caregiver Burden
Systematic review and meta-analyses of large-scale clinical
trials have shown that galantamine administration for
patients with Alzheimers disease can reduce the
amount of time caregivers spend supervising their patients
and assisting
them with ADL (activities of daily living), easing the
daily burden for caregivers. The beneficial effects
of galantamine on behavioral symptoms result in a reduction
in caregivers emotional distress, in part from
the fact that galantamine neither causes nor exacerbates
sleep disturbances, in addition to its other positive
benefits for patients: preservation of cognition, function,
and behavior, thus maintaining quality of life for both
patients with Alzheimers disease and their caregivers
(Kaufer et al., CNS Spectrum (2005): Reduction
of Caregiver Burden
in Alzheimers Disease by Treatment with Galantamine
[pdf]).

As noted above, galantamine is also available as nonprescription
herbal phytonutrient extracted primarily from the common
snowdrop (Galanthus nivalis), daffodil (Narcissus pseudonarcissus
L.), and spider lily (Lycoris radiata).

MemantineMemantine (Namenda (USA), Exiba, Axura) is a
recently approved (October 2003) new class of agent,
an NMDA (N-methyl-D-aspartate) receptor antagonist,
regulating the activity of glutamate (glutamic acid),
an amino acid with an essential role in in the neural
pathways associated with learning and memory. Memantine's
benefits in Alzheimer's disease is thought to be via
partially blocking NMDA receptors to protect cells against
excess glutamate overstimulation of NMDA receptors (which
leads to neuronal cell dysfunction / disruption and
cell death), an action wholly distinct from the acetylcholine
boosting mechanism of the acetylcholinesterase inhibitors.

The evidence shows that patients on memantine scored
higher on measures of cognition, daily function (activities
of daily living - eating, walking, toileting, bathing
and dressing) and global performance, with relatively
mild side effects (typically, dizziness, confusion,
headache and constipation), compared to those on placebo.

Numerous clinical studies (see the systematic review
of seven RCTs (1532 people) of Areosa et al. (Cochrane
Database Syst Rev (2005; last update 2004): Memantine
for Dementia) have demonstrated memantine's
efficacy in Alzheimer's disease, both as monotherapy,
and in dual therapy in patients on continuous donepezil
therapy, and it demonstrates significant improvement
of cognitive performance in vascular dementia. In addition,
its safety and tolerability are exceptional, with incidence
of premature withdrawals from adverse events no greater
than placebo, and overall low incidence of any total
adverse events.

And the 2006 Cochrane review update (McShane et al.,
Cochrane Database Syst Rev (2006): Memantine
for dementia) confirmed a small but significant
beneficial effect of memantine on cognition, activities
of daily living, and behavior, supported by clinical
impression of change, in moderate to severe Alzheimer's
disease, while in mild to moderate disease there was
evidence of a marginal beneficial effect at six months
on intention-to-treat cognition which was barely detectable
clinically, with no effect on behaviour, activities
of daily living or observed-case analysis of cognition;
in addition, patients taking memantine were slightly
less likely to develop agitation in both mild to moderate
and moderate to severe disease, but no evidence either
way about whether it has an effect on already-present
agitation. However, more recently, the limitation of
memantine to the moderate to severe setting has been
questioned: Elaine Peskind and coresearchers assessed
the safety and efficacy of memantine in patients with
mild to moderate Alzheimer's disease, finding that memantine
resulted in significantly better outcomes than placebo
on measures of cognition, global status, and behavior,
and with good tolerability (Am J Geriatr Psychiatry
(2006): Memantine
Treatment in Mild to Moderate Alzheimer Disease: A 24-Week
Randomized, Controlled Trial).

Memantine has been available in Germany since 1982 with
no reports of serious adverse events, and was approved
in 2002 by the European Medicines Agency (EMEA) for
the treatment of moderately severe to severe Alzheimer's
disease, with comparable approval in the US in 2003
for the treatment of moderate to severe Alzheimer's
disease.

(new)Memantine + Galantamine
The potential to modulate in Alzheimer's disease both
acetylcholine and glutamate pathways by galantamine
and memantine, respectively, presents a novel treatment
strategy for the management of mild to moderately severe
Alzheimer's disease, based on pharmacokinetic and pharmacodynamic
as well as ongoing observation studies (as noted by
George Grossberg et al., J Clin Pharmacol (2006): Rationale
for Combination Therapy With Galantamine and Memantine
in Alzheimer's Disease), and galantamine, among
the other acetylcholinesterase (AChE) inhibitors (AChEIs),
is of particular interest because of its dual mechanism
of action, postulated to be both an AChEI and an allosteric
modulator of nicotinic receptors, the latter activity
therefore overlapping with the modulation of NMDA (N-methyl-D-aspartate)
and nicotinic receptors that is the scope of memantine's
own activity; thus modulation of NMDA and nicotinic
receptors by memantine and galantamine, as well as of
the acetylcholine pathway, with galantamine augmenting
memantine's glutamatergic noise suppression while simultaneously
enhancing the physiologic glutamatergic signal, may
provide an optimal combination therapy for Alzheimer's
disease, especially as cholinergic and glutamatergic
neurotransmitter systems appear to share a close functional
relationship and role in the pathogenesis of Alzheimer's
(see Hugo Geerts & George Grossberg, J Clin Pharmacol
(2006): Pharmacology
of Acetylcholinesterase Inhibitors and N-methyl-D-aspartate
Receptors for Combination Therapy in the Treatment of
Alzheimer's Disease).

Are AChEIs Effective? - The
Controversy

The
Case Against Efficacy
Recently a controversy has developed around the issue
of whether the AChEIs ([acetyl]cholinesterase inhibitors:
donepezil, rivastigmine, and galantamine) demonstrate
sufficient sound scientific evidentiary foundation to
recommend them for the treatment of Alzheimer's Disease/Dementia.
Several studies and one national development (in the
UK) have been the focal point of the controversy.

An earlier systematic review by German researchers Kaduszkiewicz
et al. (Fortschr Neurol Psychiatr (2004): Doubtful
Evidence for the Use of the Cholinesterase Inhibitor
Donepezil in Patients with Dementia - a Systematic Review
[in German: Fragliche Evidenz für den Einsatz des
Cholinesterasehemmers Donepezil bei Alzheimer-Demenz
- eine systematische Übersichtsarbeit]) drew two
conclusions : (1) that the evidence for the use of donepezil
in moderate to severe Alzheimer's Disease is lacking
due to, according to the researchers, severe methodological
deficiencies; (2) that the clinical relevance of the
postulated positive results [of efficacy of the cholinesterase
inhibitors in the treatment of Alzheimer's Disease]
would have to be questioned even if the trials had been
conducted in a methodologically sound fashion.

These controversial conclusions were followed by their
more recent systematic review (Kaduszkiewicz et al.,
BMJ (2005): Cholinesterase
inhibitors for patients with Alzheimer's disease: systematic
review of randomised clinical trials) which
concluded after review of 22 RCTs that the scientific
basis for recommendations of cholinesterase inhibitors
for the treatment of Alzheimer's disease is questionable
due to (a) flawed methodology and (b) small clinical
benefits (similarly, Therapeutics Initiative (Therapeutics
Letter (2005): Drugs
for Alzheimer's Disease) concluded that donepezil
has not been demonstrated to improve outcomes of importance
to patients and caregivers (e.g. institutionalization
or disability), while rivastigmine and galantamine have
not been studied for these outcomes). Evidencewatch
has reviewed the conclusions of Kaduszkiewicz et al.,
and as we discuss below, we suggest that the conclusions
themselves are in error primarily due to their own severe
methodological deficiencies.

Note that these preliminary recommendations essentially
represent the withdrawal of the previous NICE guidance
in favor of the use of donepezil (Aricept) rivastigmine
(Exelon) and galantamine ( Razadyne, formerly
Reminyl) mild to moderate Alzheimer's disease
(AD) under prescribed circumstances (NICE (2001): Drugs
for Alzheimer's Disease - full guidance).

(updated)The Case for Efficacy
It is imperative however to understand that NICE found
in favor of the clinical efficacy
of the cholinesterase inhibitors in mild to moderate
Alzheimer's Disease and of memantine in moderately severe
to severe Alzheimer's disease, but disputes only their
cost effectiveness (note an earlier study
of donepezil alone, the so-called AD2000 study from
the AD2000 Collaborative Group (Courtney et al., Lancet
(2004): Long-term
donepezil treatment in 565 patients with Alzheimer's
disease (AD2000): randomised double-blind trial),
also concluded that it is not cost effective, with benefits
below minimally relevant thresholds, and went on to
state that more effective treatments than cholinesterase
inhibitors are needed for Alzheimer's disease). And
Kaiser et al. (Med Klin (Munich) (2005): Donepezil
in Patients with Alzheimers Diseasea Critical
Appraisal of the AD2000 Study, in German: Donepezil
bei Patienten mit Alzheimer-Demenz Die AD2000-Studie).
Donepezil in Patients with Alzheimers Disease - a Critical
Appraisal of the AD2000 Study) despite questioning the
validity of the AD2000 trial on the basis of its low
statistical power to detect a significant difference
between both treatments, and also because no true intention-to-treat
analysis based on the first randomization was presented,
nonetheless concluded that the beneficial effects on
patient-relevant outcomes, and consequently the widespread
use of cholinesterase inhibitors in patients with Alzheimer's
disease, is not supported by current evidence.

Evidencewatch notes further that the assessment
of the cost effectiveness of galantamine was solely
based of the prescription item (as Razadyne,
formerly Reminyl, from Janssen-Ortho, hereafter
galantamine-prescription); unrecognized by NICE is the
fact that galantamine is alternatively available in
equivalent pharmaceutical grade as the OTC (over-the-counter)
herbal galantamine (galanatamine-OTC) but at approximately
one third of the cost of the prescription item, and
we would argue based on the AHEAD modeling framework
used by NICE for determining cost effectiveness, that
galantamine-OTC, against the other agents and against
galantamine-prescription, if considered would have demonstrated
both clinical efficacy and cost effectiveness, and therefore
even if all other findings of NICE are uncontested,
their conclusion on the status of galantamine is in
error.

Systematic Reviews & Meta-analyses
- Efficacy:
Cochrane
There are several problems associated with the Kaduszkiewicz
et al. study, the most global being that it appears
against the evidence of many high-quality systematic
reviews and meta-analysis: among these, the Cochrane
reviews. Birks & Harvey, (Cochrane Database Syst
Rev (2003): Donepezil
for dementia due to Alzheimer's disease (Cochrane Review)),
found that people with mild, moderate or severe dementia
due to Alzheimer's disease treated for periods of 12,
24 or 52 weeks with donepezil experienced benefits in
cognitive function, activities of daily living and behavior,
and although no significant changes were measured on
a patient-rated quality of life scales, the researchers
note that the instrument used was crude and possibly
unsuited to the task, and in addition although more
evidence is still needed for the economic efficacy of
donepezil, clinical efficacy is confirmed. Birks et
al., Cochrane Database Syst Rev (2000): Rivastigmine
for Alzheimer's disease (Cochrane Review)),
found that rivastigmine appears to be beneficial for
people with mild to moderate Alzheimer's disease, with
comparisons with placebo showing improvements in cognitive
function, activities of daily living, and severity of
dementia with daily doses of 6 to 12 mg. Loy & Schnieder
(Cochrane Database Syst Rev (2006): Galantamine for Alzheimer's disease (Cochrane Review)),
found consistent positive effects for galantamine for
trials of 3 to 6 months duration for doses above 8mg/d
for mildly to moderately impaired outpatients (although
galantamine's effect on more severely impaired subjects
has not yet been assessed), and galantamine's safety
profile is similar to that of other cholinesterase inhibitors
with respect to cholinergically mediated gastrointestinal
symptoms, with doses of 16 mg/d best tolerated, and
with this dose showing statistically indistinguishable
efficacy with higher doses, and finally, that longer
term use of galantamine has not been assessed in a controlled
fashion, and galantamine's effect on more severely impaired
subjects has not yet been assessed. Areosa et al. (Cochrane
Database Syst Rev (2005): Memantine
for dementia (Cochrane Review)), found a small
beneficial effect of memantine at six months in moderate
to severe Alzheimer's disease but the beneficial effect
on cognition in patients with mild to moderate vascular
dementia was not detectable on global assessment at
six months; whether memantine has any effect in mild
to moderate Alzheimer's disease is unknown.

(new) And Sophie Gillette-Guyonnet
and colleagues investigated the effect of cholinesterase
inhibitors on three clinically relevant domains (rapid
cognitive decline, institutionalization, and weight
loss) in patients with Alzheimer's disease, in the unique
environment of all patients having been recruited and
followed in the same center, with the same management
care plan, and the same medical team, finding that the
risk of rapid cognitive deterioration was significantly
decreased in patients taking cholinesterase inhibitors
for at least 1 year compared to untreated patients,
with a potential benefit of cholinesterase inhibitors
use also found on institutionalization and weight loss
after 1 year of follow-up, thus demonstrating a clinically
significant improvement in patient outcome over time
(J Gerontol A Biol Sci Med Sci (2006): Outcome
of Alzheimer's Disease: Potential Impact of Cholinesterase
Inhibitors).

(new) Similarly, Pierre
Tariot, an Alzheimer's specialist at the University
of Rochester Medical Center in New York, recently reviewed
the efficacy issue, finding that (1) although memantine
is currently the only agent approved for use in the
moderate to severe setting, monotherapy regimens involving
a ChEI or memantine have been shown to slow the progression
of cognitive symptoms in patients with Alzheimer's disease;
(2) combination therapy involving memantine plus a cholinesterase
inhibitor yields increased cognitive benefits relative
to cholinesterase inhibitor monotherapy, thought to
be attributable to the distinct therapeutic mechanisms
associated with NMDA receptor open-channel antagonists
and cholinesterase inhibitors; (3) the therapeutic effects
of these antidementia agents are not limited to cognition,
also improving outcomes related to patient functioning
and behavior, two domains of likely great significance
for patients and caregivers; (4) antidementia agents
may significantly delay nursing home placement; and
(5) that in summary, both cholinesterase inhibitors
and memantine provide substantial benefits extending
across the spectrum of symptoms of Alzheimer's disease,
improving outcomes for those affected by this debilitating
condition, either directly or indirectly (P Tariot,
J Clin Pyschiatry (2006): Contemporary
issues in the treatment of Alzheimer's disease: tangible
benefits of current therapies).

The Methodological Deficiencies
of KaduszkiewiczKaduszkiewicz et al.
criticize the Cochrane research on a number of grounds.
One claim is that there is
no correction for multiple outcomes. But as Jacqueline
Birks (Coordinating Editor of the Cochrane Dementia
and Cognitive Improvement Group, and herself a medical
statistician) points out (BMJ (2005): The
Cochrane reviews of the cholinesterase inhibitors
[Rapid Response to: Kaduszkiewicz et al.), nearly all
trials surveyed by Cochrane show a significant effect
for the drug for the primary outcomes, which are also
highly significant in the meta-analyses, so that no
correction for multiple comparisons would change this
in any way. Furthermore, even if a post hoc adjustment
for multiple comparisons in the absence of pre-specified
primary outcomes, like the well-known Bonferroni correction
(also known as Fisher's method of alpha splitting),
were applied to the multiple pooled outcomes in the
Cochrane meta-analyses, the effects of cholinesterase
inhibitors would remain statistically significant (as
noted by McShane & Schneider (also
Coordinating Editors of the Cochrane Dementia and Cognitive
Improvement Group), BMJ (2005): The
baby has been thrown out with the bath water
[Rapid Response to: Kaduszkiewicz et al. Furthermore,
going beyond McShane & Schneider's observation concerning
the Bonferroni correction, Evidencewatch
has confirmed that neither under Bonferroni correction
nor naïve Monte Carlo simulation applied to the
multiple pooled outcomes in the Cochrane meta-analyses
is the conclusion of statistical significance for the
positive effects of cholinesterase inhibitors on Alzheimer's
disease materially affected.

(updated)Alzheimer's Watch:
Conclusions on the Value / Efficacy of Current AD Therapies
In sum, therefore, Evidencewatch
has (1) reviewed the arguments of Kaduszkiewicz
et al. with respect to putative deficiencies
in the Cochrane meta-analyses of the efficacy
of the cholinesterase inhibitors in the treatment of
Alzheimer's disease, and does not find these arguments
cogent, resting on misperceptions of and illicit deductions
from that literature, moreover having successfully been
responded to and refuted by Birks, McShane and Schneider
(see above), and furthermore (2) we find these
arguments against the balance of the evidence of the
collective weight and findings of numerous independent
methodologically high-quality systematic reviews and
meta-analyses, cited above, and for these reasons Evidencewatch
concludes upon the best evidence that both the cholinesterase
inhibitors and memantine have demonstrated efficacy
in the treatment of Alzheimer's disease / dementia.

Evidencewatch Commentary: Gingko
Although it is often stated by clinicians that herbal
nonprescription Ginkgo products differ in purity and concentrations
of active ingredients compared with the high purity extract
(EGb 761 used in most RCTs, Evidencewatch notes that some
quality herbal providers do indeed market this formulation
(for example, in the US, Life Extension Foundation (LEF)).

In addition, rigorous systematic reviews have found for
the efficacy of Gingko biloba as demonstrating statistically
significant mild effectiveness in the treatment of cognitive
deficit in Alzheimer's disease (Birks & Grimley, Cochrane
Database Syst Rev (2002): Ginkgo
biloba for cognitive impairment and dementia);
see also Santos-Neto et al., eCAM (2006): The
Use of Herbal Medicine in Alzheimer's DiseaseA Systematic
Review), although it has remained until recently
whether besides benefiting cognitive deficit, Ginkgo reduces
the actual development of Alzheimer's. Fortunately, precisely
this question has been addressed in the RCT by researchers
from the Catholic University of Sacred Heart (Mazza et
al., Eur J Neurol (2006): Ginkgo
biloba and donepezil: a comparison in the treatment of
Alzheimer's dementia in a randomized placebo-controlled
double-blind study) who assessed the efficacy
of the Ginkgo biloba special extract Flavogin (160 mg/daily),
from Baif International (Italy)), an EGb 761 formulation,
in patients with Alzheimer type mild to moderate dementia
in slowing down the disease's degenerative progression
and the patients' cognitive impairment compared with 5
mg/daily donepezil (Aricept), and placebo. The study found
no evidence of relevant differences in the efficacy of
Flavogin/EGb 761 and donepezil in the treatment of mild
to moderate Alzheimer's dementia.

Evidencewatch Commentary:
Issue of Safety of Gingko
Although numerous case reports have alluded to potential
hemorrhagic adverse events from the intake of Gingko biloba
preparations, postulated on its activity with platelet
aggregation and blood coagulation, no studies of sufficient
methodological power provide any confirmation to these
largely anecdotal speculations, and the matter has been
decisively address by the recent RCT of Kohler et al.
(Blood Coagul Fibrinolysis (2004): Influence
of a 7-day treatment with Ginkgo biloba special extract
EGb 761 on bleeding time and coagulation: a randomized,
placebo-controlled, double-blind study in healthy volunteers
) who investigated the influence of the Ginkgo biloba
special extract EGb 761 on hemostasiological parameters,
finding that among the 29 coagulation and bleeding parameters
they assessed, "none showed any evidence of an inhibition
of blood coagulation and platelet aggregation through
EGb 761. Furthermore, the study did not reveal any evidence
to substantiate a causal relationship between the administration
of EGb 761 and hemorrhagic complications."

Evidencewatch Commentary: Vitamin
E
Note that quite recently there has been concern over high-dose
Vitamin E and increased mortality risk, as per Miller
et al. (Ann Intern Med (2005): Meta-analysis:
high-dosage vitamin E supplementation may increase all-cause
mortality ). However, in this study the reviewed
trials testing high dosages were of adults with chronic
diseases, and therefore these findings cannot viably be
seen as generalizable to healthy adults; further research
is required to be dispositive on this issue.

(new)
Folate and B Vitamins
Both elevated blood concentrations of homocysteine, and
low-normal concentrations of the B vitamins B-12 and B-6
and folate are candidate risk factors for Alzheimer's
disease (AD Smith, Nutr Health (2006: Prevention
of dementia: a role for B vitamins?). Smith's
review of 77 cross-sectional studies on > 34,000 subjects
and 33 prospective studies on > 12,000 subjects in
the literature up to the end of 2005 found (1) associations
between cognitive deficit or dementia and homocysteine
and/or B vitamins, and (2) that elevated plasma total
homocysteine is a strong prognostic marker of future cognitive
decline.

(updated)
NSAIDs
Recent research in Alzheimer's disease and dementia has
sought to understand and elucidate the inflammatory pathways
involved in Alzheimers disease, and the alteration or
inhibition of these pathways, the latter seen as a potential
therapeutic intervention targeting the underlying cause
of Alzheimer's disease rather than its symptoms, unlike
the current use of the acetylcholinesterase inhibitors
to prolong cognitive function through increased synaptic
activity, without however providing underlying neuroprotection,
that is, prevention of neuronal death (Stuchbury &
Münch, J Neural Transm (2005): Alzheimer's
associated inflammation, potential drug targets and future
therapies ).

(new)
Antioxidants and Polyphenols
Resveratrol appears to modulates multiple mechanisms of
Alzheimer's disease pathology and neuronal degeneration
(TS Anekonda, Brain Res Rev (2006): ResveratrolA
boon for treating Alzheimer's disease?). In addition,
Qi Dai at the Vanderbilt-Ingram Cancer Center and colleagues
(Am J Med (2006): Fruit
and Vegetable Juices and Alzheimers Disease: The
Kame Project) tested whether consumption of fruit
and vegetable juices with a high concentration of polyphenols
decreases the risk of incident probable Alzheimers
disease in the Kame Project cohort (population-based prospective
study of prospective study conducted among Japanese Americans
living in King County, Washington), finding that fruit
and vegetable juices may play an important role in delaying
the onset of Alzheimers disease, particularly among
those who are at high risk for the disease (those who
were not physically active or with a certain apolipoprotein
E allele), and that this may be in part due to the role
played by hydrogen peroxide (H2O2)-mediated
ß-amyloid peptide oxidative damage caused by the
in the pathogenesis of Alzheimers disease. This
is in keeping with earlier findings showing that polyphenols
from apple and citrus juices, such as quercetin, cross
the blood-brain barrier and exert neuroprotection against
H2O2..with
quercetin from apple juice conferring stronger neuroprotection
than vitamin C (see Daniela Ortiz & Thomas Shea at
the University of Massachusetts, J Alzheimers Dis (2004):
Apple
juice prevents oxidative stress induced by amyloid-beta
in culture [pdf]; HJ Heo and CY Lee at Cornell University,
J Agric Food Chem (2004):Protective
Effects of Quercetin and Vitamin C against Oxidative Stress-Induced
Neurodegeneration.

And Yvonne Freund-Levi at the Karolinska Institutet and
co-researchers in the OmegAD Study examined the effects
of dietary omega-3 fatty acid supplementation on cognitive
functions in patients with mild to moderate Alzheimer's
disease finding that although such supplementation did
not delay the rate of cognitive decline, there were positive
effects in a small group of patients with very mild Alzheimer's
disease, defined as MMSE >27 points (Arch Neurol (2006):
Omega-3
Fatty Acid Treatment in 174 Patients With Mild to Moderate
Alzheimer Disease: OmegAD Study).

One possible confounding factor in these and related studies
may be the issue of melatonin levels, given that the decline
in melatonin production in aged individuals has been hypothesized
as a primary contributing factor for the development of
age-associated neurodegenerative diseases, and given that
melatonin has been shown to be effective in arresting
neurodegenerative phenomena seen in experimental models
of Alzheimer's disease. So in the review by V. Srinivasan
and coresearchers (Nneurotox Res (2005): Role
of melatonin in neurodegenerative diseases), it
was concluded that therapeutic trials with melatonin have
been effective in slowing the progression of Alzheimer's
disease (but not of Parkinson's disease), probably via
preservation of mitochondrial homeostasis, reduction of
free radical generation, increasing mitochondrial glutathione
levels, and safeguarding proton potential and ATP synthesis
by stimulating complex I and IV activities. And V. Srinivasan
and colleagues have more recently followed up this study
and concluded their from review of the literature that
melatonin may have potential value in both the prevention
and treatment of Alzheimer's disease and other neurodegenerative
disorders (Behav Brain Funct (2006): Melatonin
in Alzheimer's disease and other neurodegenerative disorders).

Similarly, Ying-Hui Wu and Dick Swaab in their review
(J Pineal Res (2006): The
human pineal gland and melatonin in aging and Alzheimer's
disease) concluded that there is evidence that
a dysfunction of the sympathetic regulation of pineal
melatonin synthesis by the suprachiasmatic nucleus (SCN)
is responsible for melatonin changes during the early
AD stages, and that reactivation of the circadian system
by means of light therapy and melatonin supplementation
to restore the circadian rhythm and to relieve the clinical
circadian disturbances has shown promising positive results.
And Almagan Altun & B Uqur-Altun (Int J Clin Practice
(2006): Melatonin:
therapeutic and clinical utilization), noting
that melatonin not only plays an important role in the
regulation of circadian rhythms but also acts as an antioxidant
and neuroprotector, concluded that in both in vivo and
in vitro studies of Alzheimer's disease, melatonin has
been shown to be effective in arresting neurodegenerative
phenomena.

Finally, another recent review by Jian-zhi Wang &
Ze-fen Wang (Acta Pharmacologica Sinica (2006): Role
of melatonin in Alzheimer-like neurodegeneration)
noting melatonin's important role in aging and Alzheimer's
disease as an antioxidant and neuroprotector, with a profound
reduction in this hormone in Alzheimer's patients, concluded
that melatonin supplementation improves sleep, ameliorates
sundowning, slows down the progression of cognitive impairment
in Alzheimer's patients, protecting neuronal cells from
Aß-mediated toxicity via antioxidant and anti-amyloid
properties, arresting the formation of amyloid fibrils
by a structure-dependent interaction with Aß, attenuating
Alzheimer-like tau hyperphosphorylation; additionally,
melatonin also plays a role in protecting cholinergic
neurons and in anti-inflammation, all suggesting its potential
in the prevention or treatment of Alzheimer's disease.
All these studies suggest a critical beneficial role of
melatonin supplementation in the treatment of Alzheimer's
disease and may help to explain known phenomenon in that
disorder such as sundowning, or sundown
syndrome, where some Alzheimer's and dementia patience
experience behavioral symptoms clustered mostly in the
afternoon and evening (Ladislav Volicer et al., Am J Psychiatry
(2001): Sundowning
and Circadian Rhythms in Alzheimers Disease).

(new)Statins
The role of statins in Alzheimer's therapeutics is controversial,
but some recent RCTs have found for significant benefit:
so DL Sparks and co-researchers (Acta Neurol Scand Suppl
(2006): Statin
therapy in Alzheimer's disease) conducted a double-blind,
placebo-controlled, randomized trial with a 1-year exposure
to once-daily (80 mg) atorvastatin calcium (Lipitor),
concluding that atorvastatin therapy may be of benefit
in the treatment of mild-to-moderately affected Alzheimer's
patients, but that the degree of benefit might be predicated
on earlier treatment, and that atorvastatin may slow the
progression of mild-to-moderate Alzheimer's disease, thereby
prolonging the quality of life. And given the growing
evidence for the role of vascular factors in Alzheimers
disease, mixed dementia (Alzheimers disease with
cerebrovascular disease), and of course vascular dementia,
K Alagiakrishnan and colleagues in Canada reviewed the
possibility of preventing or delaying the expression and
progression of dementia by changing modifiable vascular
risk factors (Postgrad Med J (2006): Treating
vascular risk factors and maintaining vascular health:
Is this the way towards successful cognitive ageing and
preventing cognitive decline?), concluding that
the practical and effective treatment of vascular risk
factors - particularly but not only blood pressure and
serum cholesterol - in middle age or even in old age may
be the most effective preventive measure available for
the prevention of dementia at this time

Reality
Orientation /
Cognitive Stimulation TherapyReality Orientation (RO) or Cognitive Stimulation
Therapy (CST) operate through the presentation of
orientation information (time, place and person-related),
in order to provide the person with a greater understanding
of their surroundings, possibly resulting in an improved
sense of control and self-esteem. Spector et al. (Cochrane
Database Syst Rev (2000): Reality
orientation for dementia ) concluded that "there
is some evidence that RO has benefits on both cognition
and behavior for dementia sufferers . . . [and] it appears
that a continued programme may be needed to sustain potential
benefits".